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Interferons Direct an Effective Innate Response to Legionella pneumophila Infection*

Open AccessPublished:August 31, 2009DOI:https://doi.org/10.1074/jbc.M109.018283
      Legionella pneumophila remains an important opportunistic pathogen of human macrophages. Its more limited ability to replicate in murine macrophages has been attributed to redundant innate sensor systems that detect and effectively respond to this infection. The current studies evaluate the role of one of these innate response systems, the type I interferon (IFN-I) autocrine loop. The ability of L. pneumophila to induce IFN-I expression was found to be dependent on IRF-3, but not NF-κB. Secreted IFN-Is then in turn suppress the intracellular replication of L. pneumophila. Surprisingly, this suppression is mediated by a pathway that is independent of Stat1, Stat2, Stat3, but correlates with the polarization of macrophages toward the M1 or classically activated phenotype.
      Legionella pneumophila, the causative agent of Legionnaires' Disease, remains an important cause of human morbidity (
      • Sabrià M.
      • Campins M.
      ). Like other pulmonary pathogens, L. pneumophila subverts host immunity through its capacity to replicate within macrophages. Genetic studies have mapped L. pneumophila virulence and immune evasion to the Dot-Icm type IV secretion system (reviewed in Refs.
      • Fortier A.
      • Diez E.
      • Gros P.
      ,
      • Neild A.L.
      • Roy C.R.
      ,
      • Segal G.
      • Feldman M.
      • Zusman T.
      ). Subsequent studies identified “effector” proteins, which the Dot-Icm system injects into host cells, enabling the bacteria to avoid lysosomal targeting and establish a unique replicative compartment (
      • Ninio S.
      • Roy C.R.
      ).
      The ability of murine macrophages to resist L. pneumophila infection has been attributed to several redundant innate sensor and response systems. For example, the unique susceptibility of macrophages from A/J mice to L. pneumophila infection has been mapped to Naip5/Birc1e (
      • Fortier A.
      • Diez E.
      • Gros P.
      ,
      • Losick V.P.
      • Stephan K.
      • Smirnova II
      • Isberg R.R.
      • Poltorak A.
      ). Subsequent studies determined that the Naip5 sensor functioned upstream of Ipaf in its capacity to recognize L. pneumophila flagellin, culminating in inflammasome activation (
      • Lightfield K.L.
      • Persson J.
      • Brubaker S.W.
      • Witte C.E.
      • von Moltke J.
      • Dunipace E.A.
      • Henry T.
      • Sun Y.H.
      • Cado D.
      • Dietrich W.F.
      • Monack D.M.
      • Tsolis R.M.
      • Vance R.E.
      ,
      • Molofsky A.B.
      • Byrne B.G.
      • Whitfield N.N.
      • Madigan C.A.
      • Fuse E.T.
      • Tateda K.
      • Swanson M.S.
      ,
      • Ren T.
      • Zamboni D.S.
      • Roy C.R.
      • Dietrich W.F.
      • Vance R.E.
      ,
      • Sutterwala F.S.
      • Ogura Y.
      • Zamboni D.S.
      • Roy C.R.
      • Flavell R.A.
      ). The inflammasome directs the caspase 1-dependent secretion of interleukin (IL)
      The abbreviations used are: IL
      interleukin
      IFN
      interferon
      JAK
      Janus kinases
      STAT
      Signal Transducers and Activators of Transcription
      WT
      wild type
      MOI
      multiplicity of infection
      GFP
      green fluorescent protein
      IFNAR
      IFN-α receptor
      IFNGR
      IFN-γ receptor
      BMM
      bone marrow-derived murine macrophages.
      2The abbreviations used are: IL
      interleukin
      IFN
      interferon
      JAK
      Janus kinases
      STAT
      Signal Transducers and Activators of Transcription
      WT
      wild type
      MOI
      multiplicity of infection
      GFP
      green fluorescent protein
      IFNAR
      IFN-α receptor
      IFNGR
      IFN-γ receptor
      BMM
      bone marrow-derived murine macrophages.
      -1β and IL-18, as well as promoting pyroptosis (
      • Lightfield K.L.
      • Persson J.
      • Brubaker S.W.
      • Witte C.E.
      • von Moltke J.
      • Dunipace E.A.
      • Henry T.
      • Sun Y.H.
      • Cado D.
      • Dietrich W.F.
      • Monack D.M.
      • Tsolis R.M.
      • Vance R.E.
      ,
      • Zamboni D.S.
      • Kobayashi K.S.
      • Kohlsdorf T.
      • Ogura Y.
      • Long E.M.
      • Vance R.E.
      • Kuida K.
      • Mariathasan S.
      • Dixit V.M.
      • Flavell R.A.
      • Dietrich W.F.
      • Roy C.R.
      ,
      • Amer A.
      • Franchi L.
      • Kanneganti T.D.
      • Body-Malapel M.
      • Ozören N.
      • Brady G.
      • Meshinchi S.
      • Jagirdar R.
      • Gewirtz A.
      • Akira S.
      • Núñez G.
      ). Additional studies have implicated TLR2 and MyD88, as well as a subsequent secretion of TNF, in the innate response to L. pneumophila (
      • Ren T.
      • Zamboni D.S.
      • Roy C.R.
      • Dietrich W.F.
      • Vance R.E.
      ,
      • Coers J.
      • Vance R.E.
      • Fontana M.F.
      • Dietrich W.F.
      ,
      • Stetson D.B.
      • Medzhitov R.
      ,
      • Archer K.A.
      • Roy C.R.
      ,
      • Hawn T.R.
      • Smith K.D.
      • Aderem A.
      • Skerrett S.J.
      ,
      • Hawn T.R.
      • Berrington W.R.
      • Smith I.A.
      • Uematsu S.
      • Akira S.
      • Aderem A.
      • Smith K.D.
      • Skerrett S.J.
      ).
      Both type I (e.g. IFN-α/β) and type II (IFN-γ) IFNs play an important role in the innate response to intracellular microbes (
      • Schindler C.
      • Plumlee C.
      ). Although IFN-γ's ability to classically activate macrophages toward an M1 phenotype has been intimately associated with antibacterial activity, more recent studies have also ascribed antibacterial activity to IFN-I (
      • Meraz M.A.
      • White J.M.
      • Sheehan K.C.
      • Bach E.A.
      • Rodig S.J.
      • Dighe A.S.
      • Kaplan D.H.
      • Riley J.K.
      • Greenlund A.C.
      • Campbell D.
      • Carver-Moore K.
      • DuBois R.N.
      • Clark R.
      • Aguet M.
      • Schreiber R.D.
      ,
      • Park C.
      • Li S.
      • Cha E.
      • Schindler C.
      ,
      • Filipe-Santos O.
      • Bustamante J.
      • Chapgier A.
      • Vogt G.
      • de Beaucoudrey L.
      • Feinberg J.
      • Jouanguy E.
      • Boisson-Dupuis S.
      • Fieschi C.
      • Picard C.
      • Casanova J.L.
      ,
      • Decker T.
      • Müller M.
      • Stockinger S.
      ).
      Characterization of IFN's antiviral activity led to the identification of the IFN-α receptor (IFNAR), the IFN-γ receptor (IFNGR), and the JAK-STAT signaling paradigm, where STATs (Signal Transducers and Activators of Transcription) are transcription factors and JAKs (Janus Kinases) the receptor-associated kinases that activate them (
      • Schindler C.
      • Levy D.E.
      • Decker T.
      ). Specifically, IFN-γ directs the formation of a single transcription factor, the Stat1 homodimer, whereas IFN-I directs the activation of both Stat1 homodimers and ISGF-3 (IFN-stimulated gene factor 3; Stat1 + Stat2 + IRF9). Recent studies have underscored an important role for IRF-3 and IRF-7 in promoting activation of an IFN-I autocrine loop. This entails a sequential expression of IFN-β and IFN-α, and is dependent on IFNAR. This autocrine loop plays an important role in innate immunity (
      • Schindler C.
      • Levy D.E.
      • Decker T.
      ,
      • Pichlmair A.
      • Reis e Sousa C.
      ,
      • Taniguchi T.
      • Ogasawara K.
      • Takaoka A.
      • Tanaka N.
      ).
      Both IFN-γ and IFN-Is suppress L. pneumophila growth in murine macrophages (
      • Coers J.
      • Vance R.E.
      • Fontana M.F.
      • Dietrich W.F.
      ,
      • Akamine M.
      • Higa F.
      • Haranaga S.
      • Tateyama M.
      • Mori N.
      • Heuner K.
      • Fujita J.
      ,
      • Schiavoni G.
      • Mauri C.
      • Carlei D.
      • Belardelli F.
      • Pastoris M.C.
      • Proietti E.
      ). Our studies highlight a role for the IFN-I autocrine loop in the innate response to this bacterium. The ability of L. pneumophila to induce IFN-I expression was found to depend on IRF-3, yet be independent of the flagellin-Naip5 axis, as well as p50/cRel. Additionally, in contrast to the critical role Stat1 plays in the antibacterial response of IFN-γ, the ability of IFN-α to suppress L. pneumophila growth was found to be independent of both Stat1 and Stat2. Finally, the Stat1-independent protection afforded by IFN-α correlated with the induction of classically activated M1 macrophage markers.

      DISCUSSION

      Pattern recognition sensors systems evolved to detect the presence of pathogen associated molecular patterns (PAMPs) and initiate effective innate responses (
      • Pichlmair A.
      • Reis e Sousa C.
      ,
      • Trinchieri G.
      • Sher A.
      ,
      • Kawai T.
      • Akira S.
      ). Exploiting the murine system, investigators have identified two cytosolic sensors, Naip5/Birc1e and Ipaf, which specifically initiate an innate response to L. pneumophila flagellin (
      • Fortier A.
      • Diez E.
      • Gros P.
      ,
      • Lightfield K.L.
      • Persson J.
      • Brubaker S.W.
      • Witte C.E.
      • von Moltke J.
      • Dunipace E.A.
      • Henry T.
      • Sun Y.H.
      • Cado D.
      • Dietrich W.F.
      • Monack D.M.
      • Tsolis R.M.
      • Vance R.E.
      ,
      • Molofsky A.B.
      • Byrne B.G.
      • Whitfield N.N.
      • Madigan C.A.
      • Fuse E.T.
      • Tateda K.
      • Swanson M.S.
      ,
      • Ren T.
      • Zamboni D.S.
      • Roy C.R.
      • Dietrich W.F.
      • Vance R.E.
      ,
      • Zamboni D.S.
      • Kobayashi K.S.
      • Kohlsdorf T.
      • Ogura Y.
      • Long E.M.
      • Vance R.E.
      • Kuida K.
      • Mariathasan S.
      • Dixit V.M.
      • Flavell R.A.
      • Dietrich W.F.
      • Roy C.R.
      ). This entails activation of the inflammasome, leading to caspase1 dependent secretion of IL-1β and IL-18, as well as the induction of pyroptosis (
      • Lightfield K.L.
      • Persson J.
      • Brubaker S.W.
      • Witte C.E.
      • von Moltke J.
      • Dunipace E.A.
      • Henry T.
      • Sun Y.H.
      • Cado D.
      • Dietrich W.F.
      • Monack D.M.
      • Tsolis R.M.
      • Vance R.E.
      ,
      • Zamboni D.S.
      • Kobayashi K.S.
      • Kohlsdorf T.
      • Ogura Y.
      • Long E.M.
      • Vance R.E.
      • Kuida K.
      • Mariathasan S.
      • Dixit V.M.
      • Flavell R.A.
      • Dietrich W.F.
      • Roy C.R.
      ,
      • Amer A.
      • Franchi L.
      • Kanneganti T.D.
      • Body-Malapel M.
      • Ozören N.
      • Brady G.
      • Meshinchi S.
      • Jagirdar R.
      • Gewirtz A.
      • Akira S.
      • Núñez G.
      ). Curiously however, IL-1β and IL-18 do not appear to directly regulate L. pneumophila growth in macrophages (
      • Neild A.L.
      • Roy C.R.
      ,
      • Coers J.
      • Vance R.E.
      • Fontana M.F.
      • Dietrich W.F.
      ). Moreover, the Naip5-Ipaf sensor system does not seem to participate in the secretion of other cytokines that have been associated with L. pneumophila infection (
      • Coers J.
      • Vance R.E.
      • Fontana M.F.
      • Dietrich W.F.
      ,
      • Schiavoni G.
      • Mauri C.
      • Carlei D.
      • Belardelli F.
      • Pastoris M.C.
      • Proietti E.
      ).
      Evidence that L. pneumophila replicated more robustly in IFNAR1(−/−) BMMs raised the possibility that the IFN-I autocrine loop may contribute to the innate response in WT macrophages, as recently suggested (
      • Coers J.
      • Vance R.E.
      • Fontana M.F.
      • Dietrich W.F.
      ,
      • Schiavoni G.
      • Mauri C.
      • Carlei D.
      • Belardelli F.
      • Pastoris M.C.
      • Proietti E.
      ). Consistent with this, both WT and Fla− L. pneumophila potently stimulated IFN-β expression, analogous to what has been reported for L. monocytogenes, F. tularensis, as well as other microbial pathogens (
      • Stockinger S.
      • Reutterer B.
      • Schaljo B.
      • Schellack C.
      • Brunner S.
      • Materna T.
      • Yamamoto M.
      • Akira S.
      • Taniguchi T.
      • Murray P.J.
      • Müller M.
      • Decker T.
      ,
      • Hiscott J.
      • Lin R.
      • Nakhaei P.
      • Paz S.
      ,
      • Henry T.
      • Brotcke A.
      • Weiss D.S.
      • Thompson L.J.
      • Monack D.M.
      ,
      • Tam M.A.
      • Sundquist M.
      • Wick M.J.
      ). Moreover, this response is largely independent of TLRs (
      • Coers J.
      • Vance R.E.
      • Fontana M.F.
      • Dietrich W.F.
      ,
      • Stetson D.B.
      • Medzhitov R.
      ), IPS-1/MAVs (
      • Sun Q.
      • Sun L.
      • Liu H.H.
      • Chen X.
      • Seth R.B.
      • Forman J.
      • Chen Z.J.
      ), the Naip5-Ipaf-flagellin axis (Fig. 2 and Ref.
      • Coers J.
      • Vance R.E.
      • Fontana M.F.
      • Dietrich W.F.
      ), IFNAR1, and Stat1 (supplemental Fig. S3A). Mechanistic studies determined that L. pneumophila stimulated IFN-β expression was dependent on IRF-3, but not p50/c-Rel (Fig. 3). Consistent with this, IFN-β expression also appeared to be dependent on TBK-1, the kinase that activates IRF-3 (see supplemental Fig. S3B and Ref.
      • Hiscott J.
      • Lin R.
      • Nakhaei P.
      • Paz S.
      ). Previous RNAi-based studies in human epithelial cells, which do not support robust L. pneumophila growth, have also implicated IRF-3, as well as IPS-1 in L. pneumophila-stimulated IFN-I expression (
      • Opitz B.
      • Vinzing M.
      • van Laak V.
      • Schmeck B.
      • Heine G.
      • Günther S.
      • Preissner R.
      • Slevogt H.
      • N′Guessan P.D.
      • Eitel J.
      • Goldmann T.
      • Flieger A.
      • Suttorp N.
      • Hippenstiel S.
      ).
      Genetic studies excluding a role for IPS-1 in L. pneumophila-dependent IFN-β expression raised the possibility that novel host receptors may sense the cytoplasmic accumulation of bacterial nucleic acids (
      • Stetson D.B.
      • Medzhitov R.
      ,
      • Sun Q.
      • Sun L.
      • Liu H.H.
      • Chen X.
      • Seth R.B.
      • Forman J.
      • Chen Z.J.
      ,
      • Kanneganti T.D.
      • Ozören N.
      • Body-Malapel M.
      • Amer A.
      • Park J.H.
      • Franchi L.
      • Whitfield J.
      • Barchet W.
      • Colonna M.
      • Vandenabeele P.
      • Bertin J.
      • Coyle A.
      • Grant E.P.
      • Akira S.
      • Núñez G.
      ,
      • Bürckstümmer T.
      • Baumann C.
      • Blüml S.
      • Dixit E.
      • Dürnberger G.
      • Jahn H.
      • Planyavsky M.
      • Bilban M.
      • Colinge J.
      • Bennett K.L.
      • Superti-Furga G.
      ,
      • Fernandes-Alnemri T.
      • Yu J.W.
      • Datta P.
      • Wu J.
      • Alnemri E.S.
      ,
      • Hornung V.
      • Ablasser A.
      • Charrel-Dennis M.
      • Bauernfeind F.
      • Horvath G.
      • Caffrey D.R.
      • Latz E.
      • Fitzgerald K.A.
      ,
      • Roberts T.L.
      • Idris A.
      • Dunn J.A.
      • Kelly G.M.
      • Burnton C.M.
      • Hodgson S.
      • Hardy L.L.
      • Garceau V.
      • Sweet M.J.
      • Ross I.L.
      • Hume D.A.
      • Stacey K.J.
      ). However, the μg quantities of bacterial nucleic acids required to stimulate IFN-β expression and our inability to detect even traces of L. pneumophila nucleic acids in the cytoplasm of infected macrophages (data not shown) do not support this model. Thus, the identification of the innate sensor that promotes activation of the IFN-I autocrine loop during a L. pneumophila infection remains an important goal for future studies.
      Studies exploring how IFNs antagonize L. pneumophila growth revealed a correlation with polarization of macrophages to the inflammatory M1, but not M2 phenotype (Figs. 4 and 6; not shown, Ref.
      • Timmer A.M.
      • Nizet V.
      ). Curiously, even though Stat1 was shown to play a critical role in both IFN-γ-dependent M1 polarization and L. pneumophila suppression, this was not the case for IFN-α. Rather, the ability of IFN-I to impede L. pneumophila growth was found to be independent of Stat1, Stat2, and Stat3. Intriguingly, IFN-I-dependent M1 polarization was also found to be independent of these canonical STAT signaling pathways (Fig. 5), raising the possibility that these two responses are functionally related. Additional studies exploiting the more rapid kinetics of IFN-α-stimulated iNOS expression, an archetypal M1 response, revealed a similar noncanonical IFN-I dependent signaling pathway. Moreover, the relatively rapid kinetics of IFN-I stimulated iNOS expression provided an opportunity to largely exclude an important role two well characterized STAT independent signals, p38 and PI-3 kinases, in this noncanonical IFN-I response. Consistent with the possibility that these 2 kinases may not contribute to M1 polarization or L. pneumophila suppression, biochemical studies failed to reveal robust activation of p38 and PI-3 kinases in IFN-α treated macrophages. Future studies will employ additional knock-out models to more rigorously explore the nature of IFN-I stimulated signals in M1 polarization and the suppression of L. pneumophila replication.
      In summary, the innate response to L. pneumophila infection entails the activation of multiple pattern recognition systems that direct the secretion of several inflammatory cytokines, including IL-1β, IL-18, TNF, and IFN-β (
      • Lightfield K.L.
      • Persson J.
      • Brubaker S.W.
      • Witte C.E.
      • von Moltke J.
      • Dunipace E.A.
      • Henry T.
      • Sun Y.H.
      • Cado D.
      • Dietrich W.F.
      • Monack D.M.
      • Tsolis R.M.
      • Vance R.E.
      ,
      • Zamboni D.S.
      • Kobayashi K.S.
      • Kohlsdorf T.
      • Ogura Y.
      • Long E.M.
      • Vance R.E.
      • Kuida K.
      • Mariathasan S.
      • Dixit V.M.
      • Flavell R.A.
      • Dietrich W.F.
      • Roy C.R.
      ,
      • Coers J.
      • Vance R.E.
      • Fontana M.F.
      • Dietrich W.F.
      ). Although it seems likely that these pathways synergize to mount an effective innate response to L. pneumophila, IFN-I remains the single most effective cytokine in suppressing L. pneumophila growth (
      • Amer A.
      • Franchi L.
      • Kanneganti T.D.
      • Body-Malapel M.
      • Ozören N.
      • Brady G.
      • Meshinchi S.
      • Jagirdar R.
      • Gewirtz A.
      • Akira S.
      • Núñez G.
      ,
      • Coers J.
      • Vance R.E.
      • Fontana M.F.
      • Dietrich W.F.
      ).

      Note Added in Proof

      Two recently published studies suggest that RNA polymerase III directs a RIG-I–IPS-1-dependent response to microbial DNA, including that of L. pneumophila, that culminates in IFN-β expression (
      • Chiu Y.H.
      • Macmillan J.B.
      • Chen Z.J.
      ,
      • Ablasser A.
      • Bauernfeind F.
      • Hartmann G.
      • Latz E.
      • Fitzgerald K.A.
      • Hornung V.
      ).

      Acknowledgments

      We thank Dr. K. de Felipe for generating the Fla− mutant, and Dr. X. Charpentier for providing GFP-L. pneumophila, and Dr. Genhong Cheng for providing TBK-1 knockout cells.

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